Decoding myofibroblast origins in human kidney fibrosis.
Decoding myofibroblast origins in human kidney fibrosis.
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DOI：
10.1038/s41586-020-2941-1
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发表时间：
2021-01
期刊：
影响因子：
64.8
通讯作者：
Kramann R
中科院分区：
文献类型：
--
作者：
Kuppe C;Ibrahim MM;Kranz J;Zhang X;Ziegler S;Perales-Patón J;Jansen J;Reimer KC;Smith JR;Dobie R;Wilson-Kanamori JR;Halder M;Xu Y;Kabgani N;Kaesler N;Klaus M;Gernhold L;Puelles VG;Huber TB;Boor P;Menzel S;Hoogenboezem RM;Bindels EMJ;Steffens J;Floege J;Schneider RK;Saez-Rodriguez J;Henderson NC;Kramann R
肾纤维化是慢性肾脏疾病进展的标志，然而，目前还没有抗纤维化的治疗方法。这主要是因为人类肾纤维化过程中瘢痕形成细胞的起源、功能异质性和调控仍然知之甚少。在这里，我们使用单细胞RNA-seq分析了健康和纤维化人类肾脏中近端小管细胞和非近端小管细胞的转录组，以无偏倚的方法绘制了整个人类肾脏的图谱。这使得所有基质生成细胞的高分辨率定位成为可能，揭示了周细胞和成纤维细胞的不同亚群是人肾纤维化过程中形成疤痕的肌成纤维细胞的主要细胞来源。我们利用遗传命运追踪、小鼠单细胞时间序列RNA-seq和ATAC-seq实验以及人肾纤维化的空间转录组学对这些发现进行了功能性调查，以前所未有的分辨率揭示了人肾肌成纤维细胞及其成纤维细胞和周细胞前体的起源、异质性和分化。最后，我们使用这种策略来促进靶标发现，确定Nkd2是人类肾纤维化的肌成纤维细胞特异性靶标。
Kidney fibrosis is the hallmark of chronic kidney disease progression, however, currently no antifibrotic therapies exist. This is largely because the origin, functional heterogeneity and regulation of scar-forming cells during human kidney fibrosis remains poorly understood. Here, using single cell RNA-seq, we profiled the transcriptomes of proximal tubule and non-proximal tubule cells in healthy and fibrotic human kidneys to map the entire human kidney in an unbiased approach. This enabled mapping of all matrix-producing cells at high resolution, revealing distinct subpopulations of pericytes and fibroblasts as the major cellular sources of scar forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single cell RNA-seq and ATAC-seq experiments in mice, and spatial transcriptomics in human kidney fibrosis to functionally interrogate these findings, shedding new light on the origin, heterogeneity and differentiation of human kidney myofibroblasts and their fibroblast and pericyte precursors at unprecedented resolution. Finally, we used this strategy to facilitate target discovery, identifying Nkd2 as a myofibroblast-specific target in human kidney fibrosis.